scholarly journals Peripheral lymphocyte count as a surrogate marker of immune checkpoint inhibitor therapy outcomes in patients with non-small-cell lung cancer

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Ye Jin Lee ◽  
Young Sik Park ◽  
Hyun Woo Lee ◽  
Tae Yoen Park ◽  
Jung Kyu Lee ◽  
...  
Keyword(s):  
Adverse Events ◽  
Lymphocyte Count ◽  
Unmet Need ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
Peripheral Lymphocyte ◽  
Post Treatment ◽  
Before And After ◽  
Check Point Inhibitors ◽  
Nsclc Patients

AbstractDegree of expression of programmed death-ligand 1 (PD-L1) is related with Immune check point inhibitors (ICIs) response but it needs sufficient tumor tissue. There is unmet need for easily accessible and prognostic peripheral blood (PB) biomarkers. We investigated the application of serum peripheral lymphocyte count (PLC) as a predictive PB biomarker for ICI response in patients with NSCLC. We conducted a retrospective study and reviewed the patients with NSCLC who were treated with ICIs from April 1, 2016, to March 31, 2019. The PLC before and after 1 month of immunotherapy was collected. We evaluated the association between PLC and progression-free survival (PFS), overall survival (OS) and adverse events. A total of 231 patients were treated with ICIs for NSCLC. The median follow-up period was 4.7 months and the disease progressed in 138 patients (59.7%). Compared with the lowest quartile (Q1: the lowest 25%), the highest quartile (Q4: the highest 25%) of post-treatment PLC showed a significantly higher PFS (HR 0.28, 95% CI 0.16–0.52) and OS (HR 0.35, 95% CI 0.19–0.65) in the adjusted model. An association between adverse events and PLC was not observed. We revealed that an increased pre- and post-treatment PLC was associated with favorable PFS and OS with NSCLC patients treated with ICIs. PLC could be a helpful for ICI responses in NSCLC.

scholarly journals Peripheral Lymphocyte Count as a Surrogate Marker of Immune Checkpoint Inhibitor Therapy Outcomes in Patients with Non-Small-Cell Lung Cancer

2021 ◽  
Author(s):  
Ye Jin Lee ◽  
Young Sik Park ◽  
Hyun Woo Lee ◽  
Tae Yun Park ◽  
Jung Kyu Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lymphocyte Count ◽  
Unmet Need ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Peripheral Lymphocyte ◽  
Post Treatment ◽  
University Hospital

Abstract BackgroundDegree of expression of programmed death-ligand 1 (PD-L1) is related with Immune check point inhibitors (ICIs) response but is not obligate predictive marker and needs sufficient tissue. Therefore, there is unmet need for easily accessible peripheral blood (PB) biomarkers and evaluation of the prognostic value of this marker is needed. We investigated the application of serum peripheral lymphocyte count (PLC) as a predictive PB biomarker for ICI response in patients with NSCLC. MethodsWe conducted a retrospective study and reviewed the medical charts of patients with NSCLC who were treated with ICIs at Seoul National University Hospital. We evaluated the association between PLC and progression-free survival using a Cox proportional hazard model. The PLC before and after 1 month of immunotherapy was collected. The quartile groups of PLC were compared using the Kruskal-Wallis statistical test.ResultsA total of 231 patients were treated with immunotherapy for NSCLC. The median follow-up period was 4.7 months. During the follow-up period, the disease progressed in 138 patients (59.7%). The post-treatment PLC groups Q2-4 showed significantly lower disease progression than group Q1 in our adjusted model (Q4 hazard ratio: 0.41, 95% confidence interval: 0.25–0.68, p < 0.001). The overall survival also showed similar results. An association between adverse events and PLC was not observed in this study. ConclusionWe revealed that an increased post-treatment PLC was associated with favorable progression-free and overall survival with NSCLC patients treated with ICIs. Therefore, PLC could be a surrogate marker for ICI responses in NSCLC.

scholarly journals Initial evaluation of nivolumab in patients with post-operative recurrence of malignant pleural mesothelioma

2020 ◽  
Vol 50 (8) ◽  
pp. 920-925 ◽  
Author(s):  
Akifumi Nakamura ◽  
Nobuyuki Kondo ◽  
Toru Nakamichi ◽  
Ayumi Kuroda ◽  
Masaki Hashimoto ◽  
...  
Keyword(s):  
Adverse Events ◽  
Malignant Pleural Mesothelioma ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Complete Response ◽  
Post Treatment ◽  
Pleural Mesothelioma ◽  
Serious Adverse Events ◽  
Treatment Data

Abstract Background Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM in a real-world setting. Methods This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan–Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1–14 months), and median of 8 cycles (range: 2–32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed. Conclusion Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy.

scholarly journals The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody via Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events

2021 ◽  
Vol 11 ◽  
Author(s):  
Toshiya Fujisaki ◽  
Satoshi Watanabe ◽  
Takeshi Ota ◽  
Kohei Kushiro ◽  
Yusuke Sato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Continuous Administration ◽  
Free Survival ◽  
Programmed Cell Death 1 ◽  
Third Line ◽  
Nsclc Patients

ObjectivesAlthough immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.MethodsWe retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.ResultsOf 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4–NE); p = 0.031].ConclusionThe current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

Analysis of immune-mediated reactions in patients with non-small cell lung cancer treated with nivolumab and its association with effectiveness

2021 ◽  
pp. 107815522110674
Author(s):  
Susana Cortijo-Cascajares ◽  
Ana Cristina Cercós-Lletí ◽  
Sara Ortiz-Pérez ◽  
José Manuel Caro-Teller ◽  
José Miguel Ferrari-Piquero
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Strong Predictor ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Number Of Patients ◽  
Nsclc Patients

Objective To study immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients treated with nivolumab, as well as to assess whether these reactions could be predictors of further effectiveness of therapy. Methods Retrospective, observational and longitudinal study. All NSCLC patients who received nivolumab between February 2015-May 2020 were included. In terms of safety, irAEs and their severity were registered and to evaluate the effectiveness, overall survival (OS) and progression free survival (PFS) were calculated. Results 75 patients were included. 32 patients (43%) were reported irAES. Mainly the irAEs affected the skin (36%). Followed by pneumonitis (20%), gastrointestinal reactions (12%), endocrine (12%) and hepatitis (12%). Regarding severity, 92% were moderate. The median PFS was 9.49 months on the group with irAEs versus 1.99 months on the group without irAEs group (p < 0.0001). The median OS was 17.44 months versus 7.67 months respectively (p = 0.0001). According to the incidence of irAEs developed ( = > 2 vs. 1 vs. 0), the median PFS was 20.53 versus 5.35 versus 1.99 months respectively (p < 0.0001). The median OS was 23.41 versus 15.80 versus 7.67 months, respectively (p = 0.0002) Conclusion In a significant number of patients irAEs occur, generally of grade 1–2 severity, affecting mainly the skin, lungs and gastrointestinal system. We confirm that the development of irAEs in patients with NSCLC treated with nivolumab is a strong predictor of treatment effectiveness in both PFS and OS, with statistically significant results. On those patients who experience two or more immunorelated adverse events the greatest benefit has been observed.

Extended phase I study of AS1411 in renal and non-small cell lung cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13098-13098 ◽  
Author(s):  
D. A. Laber ◽  
B. S. Taft ◽  
G. H. Kloecker ◽  
P. J. Bates ◽  
J. O. Trent ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Stable Disease ◽  
Peak Plasma ◽  
Small Cell ◽  
Post Treatment ◽  
Pharmacokinetic Analysis ◽  
Small Cell Lung ◽  
Serious Adverse Events ◽  
Nsclc Patients

13098 Background: AS1411 is an oligonucleotide aptamer that binds to nucleolin, a protein expressed on the surface of tumor cells. A dose-escalating phase I trial in patients with various advanced cancers revealed no serious toxicities and consequently did not reach an MTD. There was evidence of activity, especially in renal cell carcinoma (RCC). This study has been reopened for further dose escalation to reach an optimal biological dose (OBD; unless an MTD is reached) in patients with RCC and non-small cell lung cancer (NSCLC). Methods: Patients had advanced RCC or NSCLC refractory to standard treatment. AS1411 was administered as a single continuous 7-day iv infusion, with the option of a second cycle. Patients were enrolled in cohorts of 3. If no serious toxicity was observed within 28 days, the dose was escalated to the next level. Toxicity was graded using the NCI CTCAE v3.0. The study plan was to enroll additional patients at the OBD such that a total of 12 RCC and 12 NSCLC patients received a 7-day infusion. Blood and urine samples were taken for pharmacokinetic analysis. Tumor responses were assessed every 28 days using the RECIST guidelines. Results: No serious adverse events have been observed up to a dose of 22mg/kg/day, which was associated with a mean peak plasma concentration of 1.5 μM. Response findings to date are as follows: of 5 RCC patients, 1 maintains a near-complete response 18 months after treatment, 3 have ongoing stable disease (SD; 1 at 3 months, 2 at 2 months) and a fourth had progressive disease (PD) at 2 months post-treatment; of 3 NSCLC patients, 1 has an ongoing SD and 2 had PDs at 1 month post-treatment. Recruitment and follow up continues. Conclusions: A 7-day infusion of AS1411 at 22mg/kg/day was not associated with any serious adverse events and achieved peak plasma concentrations in the range at which killing of various cancer cell lines is observed in vitro. A single further escalation is planned to reach a dose of 40mg/kg/day. Observation of additional cases of stable disease in RCC supports the previous observations of anti-cancer effects in this disease. [Table: see text]

CD4+ T cells in PBMC to predict the outcome of anti-PD-1 therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11525-11525 ◽  
Author(s):  
Hiroshi Kagamu ◽  
Ou Yamaguchi ◽  
Ayako Shiono ◽  
Atsuto Mouri ◽  
Sachiko Miyauchi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chemokine Receptors ◽  
Mononuclear Cells ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
Cell Subpopulation ◽  
Peripheral Blood Mononuclear ◽  
Significant Prolongation ◽  
Nsclc Patients

11525 Background: Antibody blockade of programmed death 1 (PD-1), has led to durable responses and significant prolongation of overall survival in metastatic cancers including non-small cell lung cancer (NSCLC). However, in clinical trials, response rates were as low as 20 %, and approximately 50 % of the patients did not achieve benefits to prolong progression free survival. These results bring us a hypothesis that there are subgroups with distinct pre-existing anti-tumor immunity resulting in different responses to anti-PD-1 therapy. We reported that effector T cells, which are capable of mediating antitumor reactivity, are primed in LNs draining growing tumors and that these T cells exclusively belong to the T cells that down-regulated CD62L (CD62Llow) subpopulation. In the absence of purified tumor antigenic proteins or peptides on many tumors, the expression of the homing molecule CD62L on T cells may serve as a surrogate marker for identifying tumor-specific immune cells. Methods: We analyzed the peripheral blood mononuclear cells (PBMC) of 50 consecutive NSCLC patients who were planned to be treated with anti-PD-1 Ab, Nivolumab after obtaining written informed consent. The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. Results: The NSCLC patients who achieved partial response (PR) or stable disease (SD) had significantly (p = 4.1x10-7) more CD62Llow CD4+ T cells in PBMC than progressive disease (PD) patients. The percentages of CD62Llow in CD4+ T cells provided sensitivity 92.9 %, and specificity 96.7 % to predict the patients who had PD. Moreover, SD patients had significantly (p = 0.0067) less regulatory T cell subpopulation than PR patients, thus, it was possible to predict PR from SD. Conclusions: These results show that the major differences in pre-existing immunity among PR, SD, and PD patients to anti-PD-1 Ab existed in CD4+ T cell balance between primed effector and regulatory T cells. Further characterization of CD62Llow CD4+ T cells including mRNA microarray, checkpoint molecules, and chemokine receptors is going on.

Sequential monitoring of circulating stromal cells from blood is predictive of progression in NSCLC patients undergoing anti-PD-L1 therapy after definitive chemoradiation therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3051-3051
Author(s):  
Daniel Adams ◽  
Alexander Augustyn ◽  
Jianzhong He ◽  
Yawei Qiao ◽  
Ting Xu ◽  
...  
Keyword(s):  
Blood Sample ◽  
Small Cell Lung Carcinoma ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Chemoradiation Therapy ◽  
Cell Lung Carcinoma ◽  
Before And After ◽  
Progression Of Disease ◽  
Nsclc Patients

3051 Background: Cancer Associated Macrophage-Like cells (CAMLs) are a recently described circulating stromal cell common in the peripheral blood of patients with solid tumors. In non-small cell lung carcinoma (NSCLC), patients with CAMLs ≥50µm after completion of chemoradiation therapy (CRT) have been shown to have worse progression free survival (PFS). However, with the recent addition of anti-PD-L1 therapies in conjunction with CRT as standard of care, it has never yet to be evaluated whether CAMLs remain predictive for monitoring progression in NSCLC patients post anti-PD-L1 therapy. Methods: A 2 year single blind prospective study was undertaken to test the relationship of ≥50µm CAMLs to PFS based on imaging in lung patients before and after induction of CRT and PD-L1. We recruited 104 patients with pathologically confirmed unresectable NSCLC Stage II (n = 14), Stage III (n = 83), Stage IV (n = 3), and locally recurrent disease (n = 4). Baseline (BL) blood samples were taken prior to start of therapy. A second time point blood sample (T1) was taken at the end of radiotherapy (~40 days). A third time blood sample (T2) was taken after induction of anti-PD-L1 therapy (e.g. Imfinizi, Keytruda, etc.). Blood was filtered by CellSieve filtration and CAMLs were quantified. Analysis by CAML size of < 49 µm or ≥50 µm was used to evaluate PFS hazard ratios (HRs) by censored univariate & multivariate analysis. Results: CAMLs were found in 87% of samples averaging 2.9 CAMLs/7.5mL sample. At BL, CAMLs ≥50 µm had similar PFS to patients with < 50 µm CAMLs (HR = 1.1 95%CI 0.6-1.95 p = 0.8661). However, after CRT (T1), patients with CAML size ≥50 µm had worse PFS (HR = 3.2, 95%CI 1.8-5.8 p = 0.0002). After induction of anti-PD-L1 therapy (T2), patients with ≥50 µm CAMLs also had worse PFS (HR = 2.8 95%CI 1.5-5.4 p = 0.0037). CAML size at BL was not accurate at predicting progression within 24 months; however ≥50 µm CAMLs after CRT or after 1 cycle of anti-PDL1 therapy was 71% accurate at predicting progression of disease. Conclusions: Our data suggests that in NSCLC, ≥50 µm CAMLs after completion of CRT or appearing after induction of anti-PD-L1 therapy appears to predict progressive disease. If validated, additional studies are needed to determine if CAMLs can serve as a significantly prognostic blood based marker for predicting survival in NSCLC patients early in the treatment regime.

The impact of prior chemotherapy (PrC) on immunotherapy outcomes in non-small cell lung cancer (NSCLC) patients: Real data from a mono-institutional study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21639-e21639
Author(s):  
Marianna Macerelli ◽  
Simona Rizzato ◽  
Marco Giavarra ◽  
Francesca Valent ◽  
Monica Cattaneo ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Real Data ◽  
Tumor Burden ◽  
Interquartile Range ◽  
Best Response ◽  
Before And After ◽  
Ecog Ps ◽  
Nsclc Patients ◽  
The Impact

e21639 Background: Immunotherapy has changed the paradigm on NSCLC treatment. No widespread and reproducible predictive biomarkers have been established. We analyzed how PrC could affect ICI outcomes. Methods: We conducted a retrospective observational study and analyzed all NSCLC patients (pts) treated with ICI (nivolumab or atezolizumab or pembrolizumab) in our institution from 2015 to 2018 and followed until January 2020. All pts had received at least one PrC. We recorded clinical features of pts both before and after ICI treatment. Results: A total of 83 pts were included, with a median age of 69 (range, 47-82). Sixty pts (73%) were male, 74 (89%) were smokers and 81 (97%) had ECOG PS 0-1. Thirteen (15.7%) pts had a immune-related toxicity (iRT, G1-G2 76.9% and G3-G4 23.1%) and 21 (25.3%) continued ICI therapy beyond progression disease (PD). Patients with a PD as best response to PrC had more probability to reach a PD with ICI (p = 0.06). Median Progression-Free Survival (PFS) on ICI was 2.9 months (interquartile range, 1.9-9.4) with no statistical difference between pts with oligo- or diffuse progression (≤ or > 5 metastasis) during PrC (p = 0.42). Corticosteroids use was associated with worse PFS (p < 0.01). Median Overall Survival (OS) was 9.1 months (interquartile range, 3.3-26.5), with a benefit for pts with a stable disease (SD) or partial response (PR) to PrC (p = 0.02), for pts who experimented iRT (p = 0.04) and who didn’t receive corticosteroids (p < 0.01). In multivariate analysis liver or brain metastases (HR 8.8, 95% CI 2.9-26.8 and HR 2.2, 95% CI 0.6-8.1), coticosteroids use (HR 3.7, 95% CI 1.3-10.5) or previous cisplatin-based chemotherapy (HR 8.4, 95% CI 2.3-30.1) were associated with worse OS. Instead, pts whit iRT (HR 0.4, 95% CI 0.1-1.3) and PR as best response to PrC (HR 0.8, 95% CI 0.3-2.0) had a better OS. Conclusions: Our study confirms literature data and suggests that PrC could affect ICI outcomes. Tumor burden seems not to influence ICI outcomes, unlike response rate to PrC. Systemic corticosteroids use and iRT predicts ICI outcomes.

Cytoprotective Effect of Tocotrienol-Rich Fraction and α-Tocopherol Vitamin E Isoforms Against Glutamate-Induced Cell Death in Neuronal Cells

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0140-0151 ◽  
Author(s):  
Thilaga Rati Selvaraju ◽  
Huzwah Khaza’ai ◽  
Sharmili Vidyadaran ◽  
Mohd Sokhini Abd Mutalib ◽  
Vasudevan Ramachandran ◽  
...  
Keyword(s):  
Vitamin E ◽  
Cell Viability ◽  
Neuronal Cells ◽  
Positive Control ◽  
Post Treatment ◽  
Mitochondrial Activity ◽  
Before And After ◽  
Pre Treatment ◽  
Tocotrienol Rich Fraction ◽  
Major Mediator

Glutamate is the major mediator of excitatory signals in the mammalian central nervous system. Extreme amounts of glutamate in the extracellular spaces can lead to numerous neurodegenerative diseases. We aimed to clarify the potential of the following vitamin E isomers, tocotrienol-rich fraction (TRF) and α-tocopherol (α-TCP), as potent neuroprotective agents against glutamate-induced injury in neuronal SK-N-SH cells. Cells were treated before and after glutamate injury (pre- and post-treatment, respectively) with 100 - 300 ng/ml TRF/α-TCP. Exposure to 120 mM glutamate significantly reduced cell viability to 76 % and 79 % in the pre- and post-treatment studies, respectively; however, pre- and post-treatment with TRF/α-TCP attenuated the cytotoxic effect of glutamate. Compared to the positive control (glutamate-injured cells not treated with TRF/α-TCP), pre-treatment with 100, 200, and 300 ng/ml TRF significantly improved cell viability following glutamate injury to 95.2 %, 95.0 %, and 95.6 %, respectively (p < 0.05).The isomers not only conferred neuroprotection by enhancing mitochondrial activity and depleting free radical production, but also increased cell viability and recovery upon glutamate insult. Our results suggest that vitamin E has potent antioxidant potential for protecting against glutamate injury and recovering glutamate-injured neuronal cells. Our findings also indicate that both TRF and α-TCP could play key roles as anti-apoptotic agents with neuroprotective properties.

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